Inherited IL-18BP deficiency in human fulminant viral hepatitis. uri icon

Overview

abstract

  • Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.

publication date

  • June 18, 2019

Research

keywords

  • Genetic Diseases, Inborn
  • Hepatitis A
  • Intercellular Signaling Peptides and Proteins
  • Massive Hepatic Necrosis

Identity

PubMed Central ID

  • PMC5886375

Scopus Document Identifier

  • 85070495019

Digital Object Identifier (DOI)

  • 10.1084/jem.20190669

PubMed ID

  • 31213488

Additional Document Info

volume

  • 216

issue

  • 8